Field of the Invention
The present application relates to multivesicular liposome (MVL) formulations of non-steroidal anti-inflammatory drugs (NSAIDs) which minimize the side effects of NSAIDs while maintaining or improving efficacy. In particular, embodiments of the invention relate to compositions comprising NSAIDs and multivesicular liposomes, and methods of administration of the same. Methods of making multivesicular liposomes containing an NSAID and their use as medicaments are also provided.
Background Information
NSAID compounds, administered orally, are effective relievers of pain and inflammation in a variety of therapeutic settings. Because of their effectiveness, the use of oral NSAIDs for the treatment of acute and chronic joint pain and inflammation is growing rapidly (Bjorkman, Am. J. Med., 107(6A):3S-10S (1999); Barnard et al., Drug Safety, 29(7):613-20 (2007); Bardou et al., Joint Bone Spine, 77(1):6-12 (2010)). NSAIDs are also widely used for the treatment of post-operative pain, typically administered either intravenously or orally. Oral NSAID treatment, however, has been linked to a variety of serious gastrointestinal complications, including peptic ulcer, digestive perforation, hemorrhage, colonic ulcer, and colitis (Hollenz et al., Dig Dis., 24(1-2):189-94 (2006); Yamagata et al., Nippon Rinsho, 65(10):1749-53 (2007); Shibuya et al., Colorectal Dis. (2009)). Gastro-intestinal (GI) symptoms can appear within the first two weeks of therapy. Therefore, patients with both acute and chronic conditions are affected (Penis et al., Pharmacoeconomics, 19(7):779-90 (2001)). GI toxicity, and the increased morbidity that results from it, account for the majority of the cost associated with NSAID therapy (Id). It threatens both the utility and economic viability of NSAID therapy for the treatment of pain and inflammation (Bjorkman, Am. J. Med., 107(6A):3S-10S (1999)). Gastro-protective co-therapy is being explored as a solution to the GI toxicity problem; however this approach is currently considered cost prohibitive (Id.).
In general, GI toxicity is attributable to the magnitude and duration of drug exposure both in the GI tract following oral dosing and with high systemic levels of drug required to achieve efficacious drug levels at the synovial site of action. The key to improving the efficacy of NSAID therapy and to reducing GI or opioid-related side effects is to develop a treatment that provides efficacious and prolonged levels of drug directly to the joint synovial cavity or surgical wound without GI or high systemic exposure. Effective NSAIDs such as diclofenac (DCF), meloxicam (MLX) and piroxicam (PRX) are typically systemically administered at doses of 100-150 mg/day, 7.5-15 mg/day, and 20 mg/day, respectively. These relatively high, side effect-inducing doses are necessary to achieve efficacious drug levels in the synovial cavity or wound site. The levels of drug achieved in the synovial cavity following systemic NSAID administration have been shown to be significantly lower than that of plasma (Bannwart et al., Int. J. Clin. Pharmacol. Therapy, 39(1):33-36 (2001); Hundal et al., Scand. J. Rheumatol., 22(4):183-187 (1993)). Chronic 100 mg/day systemic dosing of diclofenac, for instance, produces efficacious synovial fluid levels of 200 ng/mL or less. In a 25 mL synovial space (this volume would represent a diseased knee; normal volume is 2 mL), this corresponds to an intraarticular dose of approximately 5 μg, a dose easily achieved with formulations described in this herein (Fowler, Eur. J. Clin. Pharmacol., 31(4):469-472 (1986)). For more potent NSAIDs such as MLX and PRX, the synovial drug concentrations required for efficacy are expected to be much lower.
The local residence time of drug in the synovial cavity is closely related to drug efficacy (Foong et al., J. Pharm. Pharmacol., 40(7):464-468 (1988); Foong et al., J. Pharm. Pharmacol., 45(3):204-209, 15 (1993)). However, drugs are typically cleared in a matter of hours from the synovial fluid (Neander et al., Eur. J. Clin. Pharmacol., 42(3):301-305 (1992); Larsen et al., J. Pharm. Sci., 97(11):4622-4654 (2008)). Single doses of unencapsulated NSAID drugs, therefore, whether they are administered intraarticularly or orally, have limited opportunity to achieve their therapeutic effect.
Methods of making liposomes encapsulating therapeutic agents, none has been described in Hwang et al., Int. J. Pharm. 179(1):85-95 (1999); (Cullis et al., 1987, in Liposomes from Biophysics to Therapeutics (Ostro, Ed.), Marcel Deker Inc., pp. 60-65); and (Zhang, Trends in Bio/Pharm. Ind., 4:19-24 (2008)).
The instant formulations and methods address the shortcomings of current NSAID therapy and formulations and provide other advantages as well.